Studies using heterochronic parabiosis strongly indicate the existence of blood-borne factors that regulate tissue regeneration and homeostasis in an age-dependent manner. Our recent collaborative studies identified the circulating protein Growth Differentiation Factor 11 (GDF11) as a factor present in the blood of mice whose levels decline with advancing age. Further analysis in human subjects indicates that GDF11 levels similarly decline in aging humans and that higher levels of systemic GDF11 predict improved outcomes and reduced all-cause mortality in patients with stable ischemic heart disease. To determine whether manipulation of GDF11 levels might impact organismal healthspan, we raised circulating levels of GDF11 in aged mice to approximate normal GDF11 levels seen in young mice by direct injection of recombinant GDF11 protein. This intervention produced a striking reversal of age-related pathologies in multiple organ systems, including the heart, brain, and skeletal muscle. A related study found that overexpression of GDF11's ortholog in Drosophila, Myoglianin, slows age-related deterioration of climbing muscles and extends fly lifespan. Based on these data, we propose that GDF11 represents a new anti-geronic protein that holds therapeutic promise to restore more youthful function to aging tissues. In this project, we will answer questions crucial to understanding the regulation and activity of GDF11 during aging and to evaluating its possible therapeutic relevance for use in the treatment of age-related disease, including skeletal muscle dysfunction, heart failure, and neurodegeneration. In particular, we will use a unique and powerful panel of gene modified mice to identify the primary cellular source(s) of GDF11 in vivo and track dynamic changes in the numbers of these cells and their levels of production of GDF11 during aging. We also will determine the functional consequences for aging phenotypes of loss GDF11 in the identified critical cellular compartments and test the dose sensitivity and durability of GDF11's effects. Finally, we will test the impact of increasing GDF11 levels on induced and spontaneous tumorigenesis, an aging-associated phenotype not previously interrogated for an influence by geronic proteins. Together, these studies will test a paradigm-shifting hypothesis that GDF11 represents a new molecular regulator of aging whose therapeutic modulation can promote extension of healthspan in aging individuals. Success in our proposed studies has the potential to impact the development of therapeutics across multiple major diseases of aging.